UNIVERSITY OF MALTA LIFE SCIENCE RESEARCH SEMINARS Web: http://www.um.edu.mt/events/scisem/ Email: [email protected] Abstract form Title: Molecular biomarkers associated with mutant BRCA1 breast cancer patients Presenter: Nigel Borg Contact address: Tel: Fax: Email: Presentation date: ‘Fiordaliso’, President Anton Buttigieg Street, Zejtun. 79067603 n/a [email protected] 10th January 2011 Abstract Mutations in the BRCA1 (BReast CAncer 1) gene are known to predispose a person to particular types of cancer: mainly breast, ovarian, and prostate cancers. In breast cancer, mutations in the BRCA1 gene have been associated with particular responses to therapy: namely increased susceptibility to DNA-damage therapy, and microtubule-interfering agents. It has also been observed that BRCA1-mutant breast cancers tend to fall within the category of so-called triple negative breast cancers, which also tend to be of high grade and are hence more aggressive. The mutational status of BRCA1 is thus of both prognostic and therapeutic importance. However, due to the structure of the BRCA1 gene, direct sequencing is both expensive and cumbersome hence we aim to characterise a particular immunohistochemical signature indicative of a mutant BRCA1 gene. A link has been found between BRCA1 and signalling by Oestrogen Receptor a (ERa): BRCA1 attenuates the transcriptional activity of oestrogen-bound ERa, countered by activation PI3K-Akt signalling. Mutations in the BRCA1 gene result in increased ERa signalling, due to both the loss of attenuation of the signal and indirectly increased Akt signalling through PP2A, a known inhibitor of PI3K/Akt signalling which is activated by BRCA1. We aim to test the feasibility of using phosphorylated Akt (p-Akt) as a biomarker indicating a mutant BRCA1 gene. We aim to do this by (1) staining formalin-fixed paraffin-embedded triple negative breast cancer sections with a p-Akt antibody and correlating the results with mutational analysis of the same samples and (2) by investigating whether the activation of PP2A in a human breast cancer cell line bearing a mutant BRCA1 gene induces it to react in a similar way to another cell line bearing a wild type BRCA1 with respect to p-Akt levels.